The study of commensal-host interactions is a rapidly growing field. Recent advances have uncovered roles for commensal bacteria in shaping the host immune system, metabolism, and pre-disposition or protection from autoimmunity. Thus, the microbiota has emerged as novel mechanism to manipulate human health. Despite the plethora of knowledge that has been gleaned over the last several years, there is gap in our understanding of the molecular mechanisms by which the microbiota can influence these diverse host pathways. T lymphocytes are one of the key cell types that govern adaptive immune responses that lead to antigen specific immunity and immunological memory. In both the intestine and systemic body sites, the microbiota governs the development of multiple T cell subtypes including inflammatory and regulatory T cells. While much research has gone into understanding intestinal T cell biology, little focus has been placed on how the microbiota can influence systemic T cell function. Given that commensal organisms have been presence since the birth of eukaryotic life, it is likely that a sophisticated molecular machinery has evolved witin the host to balance the relationship with the microbiota and the immune system outside of the gut. Much of this machinery will only be realized if we analyze how the immune system develops in the absence of the microbiota. Animals that are born and reared in a completely sterile environment (germfree mice) are a powerful, comparative tool to begin the discovery of novel pathways within the host that govern commensal interactions. Using this approach, we have uncovered a novel gene within T lymphocytes that is dynamically regulated by the microbiota. This gene, ERDR1, has gone un- noticed to this point despite its very high level of expression with key immune cells. We present preliminary data within this proposal that demonstrates that ERDR1 is an important functionally relevant gene in T cell biology and host health. This grant proposes to better understand the mechanisms by which ERDR1 influences host health and microbial community structure.